HIGH THROUGHPUT MOLECULAR SCREENING ASSAY DEVELOPMENT
RELEASE DATE: January 20, 2004
RFA Number: RFA-RM-04-012 (Reissued for FY2005, see RFA-RM-05-011)
Department of Health and Human Services (DHHS)
PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
(http://www.nih.gov)
This RFA is developed as an NIH roadmap initiative
(http://nihroadmap.nih.gov). All NIH Institutes and Centers participate
in roadmap initiatives. The RFA will be administered by the National
Institute of Neurological Disorders and Stroke (NINDS) on behalf of the
NIH.
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.853
LETTER OF INTENT RECEIPT DATE: March 8, 2004
APPLICATION RECEIPT DATE: March 26, 2004
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations
PURPOSE OF THIS RFA
The purpose of this RFA is to encourage the use of high throughput
molecular screening (HTS) by funding the development and adaptation of
biological assays for automated screening. This is one component of the
NIH Molecular Libraries and Imaging Roadmap Initiative
(http://nihroadmap.nih.gov/molecularlibraries/index.asp). Other
components of the Initiative will support automated molecular screening
at the Molecular Libraries Screening Centers, the creation of a
chemical compound library at the Molecular Libraries Small Molecule
Repository, and the development of related technologies.
RESEARCH OBJECTIVES
High throughput molecular screening (HTS) is the automated,
simultaneous testing of thousands of distinct chemical compounds in
models of biological mechanisms or disease. Active compounds identified
through HTS can provide powerful research tools to elucidate biological
processes and to do chemical genetics, or can form the basis of
therapeutics development programs. The immense potential of HTS to
impact the understanding of biology and disease is largely untapped
because access to automated screening facilities and large compound
libraries is limited in the academic community. The NIH Molecular
Libraries Roadmap Initiative will provide unprecedented access to these
resources and allow the broad application of HTS in NIH-supported
research.
The goal of this RFA is to initiate a continuously evolving stream of
scientifically and technologically outstanding assays that can be
automated and used for screening at the Molecular Libraries Screening
Centers. It is open to all areas of biological and biomedical
research, with the goal of providing new ways to explore the functions
of major components of the cell. Funding will be provided to enable
investigators to transform promising assay protocols by demonstrating
the responsiveness and robustness required for use in HTS. The
proposed assay protocols must employ reagents and readouts that can be
used in the HTS environment. Emphasis will be placed on assays that
provide insight into targets, either cellular or molecular, that have
not been the focus of current HTS approaches.
Many of the in vitro models of biological mechanisms and disease
currently used to study the effects of specific compounds or genetic
perturbations can be adapted to high throughput formats. There are a
number of characteristics that make an assay suitable for high
throughput approaches. The assay must be robust, reproducible and have
a readout that is amenable to automated analysis. In addition, it must
be possible to miniaturize the assay to a 96-well or higher density
format. A broad range of models share these features, including
biochemical assays, cellular models and simple model organisms such as
yeast or C. elegans. This RFA will support the development of
innovative assays for use in both basic research and therapeutics
development programs, with an emphasis on novelty of approach to
biology or disease. Appropriate assays might include but are not
limited to:
o Biochemical or cell-based assays of activity or interaction involving
proteins and/or other biological molecules.
o Assays of cellular or molecular phenotypes.
o Assays using model organisms such as yeast or C. elegans.
o Assays involving mutant proteins associated with disease.
o Modulation of expression of genes of interest, including effects on
transcription, translation or RNA splicing.
Proposals should include assay development plans that are sufficient to
demonstrate reproducibility in a low-to-moderate throughput setting,
i.e., tens or hundreds of compounds, and must be feasible for
adaptation to an automated, high-throughput screening approach. For
example, it must be possible to reduce the assay to a 96-well or higher
density format, and the assay should have a simple readout.
Demonstration of feasibility for HTS must include:
o Use of reagents and readouts that can be used in an automated HTS
environment.
o Demonstration of highly reproducible responses to pharmacological
standards or other control conditions, including linearity of response,
range of response, and acceptable signal-to-noise in a 96-well or
higher density format.
o Demonstrated selectivity and reproducibility of response to a diverse
collection of at least a few hundred compounds, such as a collection of
FDA approved drugs or other bioactive molecules.
The applicant must provide a clear plan for evaluating the significance
of the active compounds obtained in a high throughput screen using the
assay. This plan should be feasible for the evaluation of a few hundred
active compounds that may be identified in a primary HTS effort. The
plan should include counter-screens and secondary screens to rule out
artifacts and prioritize active compounds for further testing.
The overall goals for the use of the proposed assay in an HTS effort
should be well defined and clearly presented. This discussion should
include the expected future use of the compounds in a follow-up
research program, either in the context of biological research or
therapeutics development.
This RFA is intended to allow development and adaptation of screening
assays for consideration for use at the NIH Molecular Libraries
Screening Centers. These centers will work collaboratively with
selected grantees funded under this RFA, as well as other outside
investigators, to adapt assays for HTS, and will apply the assays in
screening a large, diverse compound collection. Although assays
developed under this RFA will be eligible for consideration by the NIH
screening centers, funding under this RFA does not carry a commitment
by NIH to accept the assay for screening at a center. An independent
review panel will be established to select the most promising assays
for testing in the HTS centers. Grantees will be free to use the
assays developed under this RFA for screening elsewhere.
Adherence to the criteria described in the Research Objectives will be
considered in accepting applications for review. Applications that do
not meet these criteria will not be reviewed.
MECHANISM OF SUPPORT
This RFA will use the R03 Small Grant award. As an applicant you will
be solely responsible for planning, directing, and executing the
proposed project. This RFA is a one-time solicitation. Future
unsolicited, competing-continuation applications based on this project
will compete with all investigator-initiated applications and will be
reviewed according to the customary peer review procedures. The
anticipated award date is September 30, 2004. Applications that are
not funded in the competition described in this RFA may be resubmitted
as NEW investigator-initiated applications using the standard receipt
dates for NEW applications described in the instructions to the PHS 398
application.
This RFA uses just-in-time concepts. It also uses the modular
budgeting format. (see
http://grants.nih.gov/grants/funding/modular/modular.htm).
Specifically, if you are submitting an application with direct costs in
each year of $250,000 or less, use the modular budget format. This
program does not require cost sharing as defined in the current NIH
Grants Policy Statement at
http://grants2.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.
FUNDS AVAILABLE
The NIH intends to commit approximately $2 million in FY 2004 to fund
approximately 25 new R03 grants in response to this RFA. An applicant
may request a project period of up to 1 year and a budget for direct
costs of up to $50,000 per year. Although the financial plans of the
NIH provide support for this program, awards pursuant to this RFA are
contingent upon the availability of funds and the receipt of a
sufficient number of meritorious applications. This initiative may be
repeated in future years depending on the success of the program and
the availability of funds.
ELIGIBLE INSTITUTIONS
You may submit (an) application(s) if your institution has any of the
following characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges,
hospitals, and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign institutions/organizations
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to
carry out the proposed research is invited to work with their
institution to develop an application for support. Individuals from
underrepresented racial and ethnic groups as well as individuals with
disabilities are always encouraged to apply for NIH programs.
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this RFA and welcome the opportunity
to answer questions from potential applicants. Inquiries may fall into
three areas: scientific/research, peer review, and financial or grants
management issues:
o Direct your questions about scientific/research issues to:
Dr. Jill Heemskerk, Molecular Library Assays
National Institute of Neurological Disorders and Stroke/NIH/DHHS
6001 Executive Boulevard, Room 2229 (MSC 9527)
Bethesda, MD 20892-9527 (20852 for overnight couriers)
Telephone: (301) 496-1779
FAX: (301) 402-1501
Email (preferred): assays@mail.nih.gov
o Direct your questions about peer review issues to:
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke/NIH/DHHS
6001 Executive Boulevard, Room 3208 (MSC 9529)
Bethesda, MD 20892-9529 (20852 for overnight couriers)
Telephone: (301) 496-9223
FAX: (301) 402-0182
Email (preferred): assayreview@mail.nih.gov
o Direct your questions about financial or grants management matters
to:
Karen Dunlap
Grants Management Branch
National Institute of Neurological Disorders and Stroke/NIH/DHHS
6001 Executive Boulevard, Room 3248 (MSC 9537)
Bethesda, MD 20892-9537 (20852 for overnight couriers)
Telephone: (301) 496-7359
FAX: (301) 402-0219
Email (preferred): assaysgmb@mail.nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that
includes the following information:
o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this RFA
Although a letter of intent is not required, is not binding, and does
not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review
workload and plan the review.
The letter of intent is to be sent by the date listed at the beginning
of this document. The letter of intent should be sent to:
Program Director, Molecular Library Assays
National Institute of Neurological Disorders and Stroke/NIH/DHHS
6001 Executive Boulevard, Room 2136 (MSC 9527)
Bethesda, MD 20892-9527 (20852 for overnight couriers)
Telephone: (301) 496-1779
FAX: (301) 402-1501
Email (preferred): assays@mail.nih.gov
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant
application instructions and forms (rev. 5/2001). Applications must
have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS)
number as the Universal Identifier when applying for Federal grants or
cooperative agreements. The DUNS number can be obtained by calling
(866) 705-5711 or through the web site at
http://www.dunandbradstreet.com/. The DUNS number should be entered on
line 11 of the face page of the PHS 398 form. The PHS 398 document is
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in
an interactive format. For further assistance contact GrantsInfo,
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.
SUPPLEMENTARY INSTRUCTIONS: Use the PHS 398 form with the following
modifications:
o Follow instructions for preparing an R03 application at
http://grants2.nih.gov/grants/guide/pa-files/PA-03-108.html.
o Research Plan: Items a - d of the Research Plan (Specific Aims,
Background and Significance, Preliminary Studies, and Research Design
and Methods) may not exceed a total of 10 pages.
o Appendix. The appendix may include original, glossy photographs or
color images of data provided that a photocopy (may be reduced in size)
is also included within the page limits of the research plan.
Publications or other printed material should not be included in the
appendix.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications
requesting up to $250,000 per year in direct costs must be submitted in
a modular grant format. The modular grant format simplifies the
preparation of the budget in these applications by limiting the level
of budgetary detail. Applicants request direct costs in $25,000
modules. Section C of the research grant application instructions for
the PHS 398 (rev. 5/2001) at
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants. Additional information
on modular grants is available at
http://grants.nih.gov/grants/funding/modular/modular.htm.
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev.
5/2001) application form must be affixed to the bottom of the face page
of the application. Type the RFA number on the label. Failure to use
this label could result in delayed processing of the application such
that it may not reach the review committee in time for review. In
addition, the RFA title and number must be typed on line 2 of the face
page of the application form and the YES box must be marked. The RFA
label is also available at:
http://grants.nih.gov/grants/funding/phs398/labels.pdf.
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten
original of the application, including the Checklist, and three signed,
photocopies, in one package to:
Center For Scientific Review
National Institutes Of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the application and
all copies of the appendix material must be sent to:
Program Director, Molecular Library Assays
National Institute of Neurological Disorders and Stroke/NIH/DHHS
6001 Executive Boulevard, Room 2136 (MSC 9527)
Bethesda, MD 20892-9527 (20852 for overnight couriers)
APPLICATION PROCESSING: Applications must be received on or before the
application receipt date listed in the heading of this RFA. If an
application is received after that date, it will be returned to the
applicant without review.
Although there is no immediate acknowledgement of the receipt of an
application, applicants are generally notified of the review and
funding assignment within 8 weeks.
The Center for Scientific Review (CSR) will not accept any application
in response to this RFA that is essentially the same as one currently
pending initial review, unless the applicant withdraws the pending
application. However, when a previously unfunded application,
originally submitted as an investigator-initiated application, is to be
submitted in response to an RFA, it is to be prepared as a NEW
application. That is, the application for the RFA must not include an
Introduction describing the changes and improvements made, and the text
must not be marked to indicate the changes from the previous unfunded
version of the application.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR
and responsiveness by the Molecular Libraries Roadmap program staff.
Incomplete and/or nonresponsive applications will not be reviewed.
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened in accordance with the review criteria stated
below. As part of the initial merit review, all applications will:
o Undergo a process in which only those applications deemed to have the
highest scientific merit, generally the top half of the applications
under review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by an appropriate National Advisory
Council or Board.
REVIEW CRITERIA
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.
In the written comments, reviewers will be asked to evaluate the
application in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals. The
scientific review group will address and consider each of the following
criteria in assigning the application’s overall score, weighting them
as appropriate for each application.
o Significance
o Approach
o Innovation
o Investigator
o Environment
The application does not need to be strong in all categories to be
judged likely to have major scientific impact and thus deserve a high
priority score. For example, an investigator may propose to carry out
important work that by its nature is not innovative but is essential to
move a field forward.
SIGNIFICANCE: Does this study address an important problem? If the aims
of the application are achieved, how will scientific knowledge be
advanced? What will be the effect of these studies on the concepts or
methods that drive this field?
APPROACH: Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of
the project? Does the applicant acknowledge potential problem areas and
consider alternative tactics?
INNOVATION: Does the project employ novel concepts, approaches or
methods? Are the aims original and innovative? Does the project
challenge existing paradigms or develop new methodologies or
technologies?
INVESTIGATOR: Is the investigator appropriately trained and well suited
to carry out this work? Is the work proposed appropriate to the
experience level of the principal investigator and other researchers
(if any)?
ENVIRONMENT: Does the scientific environment in which the work will be
done contribute to the probability of success? Do the proposed
experiments take advantage of unique features of the scientific
environment or employ useful collaborative arrangements? Is there
evidence of institutional support?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the
following items will be considered in the determination of scientific
merit and the priority score:
FEASIBILITY FOR HTS: Although high throughput screening is outside the
immediate scope of this announcement, is it feasible to adapt the
proposed assay to a high throughput format? Is it likely that the assay
will produce reliable results in a high throughput screen?
FUTURE PLANS: Is there an adequate plan for evaluating the activities
of the compounds identified in a high throughput screen, e.g., in
secondary screens? Are there important and well-defined goals for the
use of active compounds identified using the proposed assay, either for
use as research tools or for therapeutics development?
PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of
human subjects and protections from research risk relating to their
participation in the proposed research will be assessed. (See criteria
included in the section on Federal Citations, below).
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy
of plans to include subjects from both genders, all racial and ethnic
groups (and subgroups), and children as appropriate for the scientific
goals of the research. Plans for the recruitment and retention of
subjects will also be evaluated. (See Inclusion Criteria in the
sections on Federal Citations, below).
CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals
are to be used in the project, the five items described under Section f
of the PHS 398 research grant application instructions (rev. 5/2001)
will be assessed.
ADDITIONAL REVIEW CONSIDERATIONS
BUDGET: The reasonableness of the proposed budget and the requested
period of support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: March 8, 2004
Application Receipt Date: March 26, 2004
Peer Review Date: July 2003
Council Review: September 2004
Earliest Anticipated Start Date: September 30, 2004
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
REQUIRED FEDERAL CITATIONS
HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that
applications and proposals involving human subjects must be evaluated
with reference to the risks to the subjects, the adequacy of protection
against these risks, the potential benefits of the research to the
subjects and others, and the importance of the knowledge gained or to
be gained.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm
HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of
research on hESCs can be found at http://stemcells.nih.gov/index.asp and
at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.
Only research using hESC lines that are registered in the NIH Human
Embryonic Stem Cell Registry will be eligible for Federal funding (see
http://escr.nih.gov). It is the responsibility of the applicant to
provide, in the project description and elsewhere in the application as
appropriate, the official NIH identifier(s) for the hESC line(s)to be
used in the proposed research. Applications that do not provide this
information will be returned without review.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT:
The Office of Management and Budget (OMB) Circular A-110 has been
revised to provide public access to research data through the Freedom of
Information Act (FOIA) under some circumstances. Data that are (1)
first produced in a project that is supported in whole or in part with
Federal funds and (2) cited publicly and officially by a Federal agency
in support of an action that has the force and effect of law (i.e., a
regulation) may be accessed through FOIA. It is important for
applicants to understand the basic scope of this amendment. NIH has
provided guidance at
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this RFA in a public
archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application
should include a description of the archiving plan in the study design
and include information about this in the budget justification section
of the application. In addition, applicants should think about how to
structure informed consent statements and other human subjects
procedures given the potential for wider use of data collected under
this award.
STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:
The Department of Health and Human Services (DHHS) issued final
modification to the “Standards for Privacy of Individually Identifiable
Health Information”, the “Privacy Rule,” on August 14, 2002. The
Privacy Rule is a federal regulation under the Health Insurance
Portability and Accountability Act (HIPAA) of 1996 that governs the
protection of individually identifiable health information, and is
administered and enforced by the DHHS Office for Civil Rights (OCR).
Those who must comply with the Privacy Rule (classified under the Rule
as “covered entities”) must do so by April 14, 2003 (with the exception
of small health plans which have an extra year to comply).
Decisions about applicability and implementation of the Privacy Rule
reside with the researcher and his/her institution. The OCR website
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule,
including a complete Regulation Text and a set of decision tools on “Am
I a covered entity?” Information on the impact of the HIPAA Privacy
Rule on NIH processes involving the review, funding, and progress
monitoring of grants, cooperative agreements, and research contracts
can be found at http://grants1.nih.gov/grants/guide/notice-files/NOT-
OD-03-025.html.
URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and
proposals for NIH funding must be self-contained within specified page
limitations. Unless otherwise specified in an NIH solicitation, Internet
addresses (URLs) should not be used to provide information necessary to
the review because reviewers are under no obligation to view the
Internet sites. Furthermore, we caution reviewers that their anonymity
may be compromised when they directly access an Internet site.
HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to
achieving the health promotion and disease prevention objectives of
"Healthy People 2010," a PHS-led national activity for setting priority
areas. This RFA is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2010" at
http://www.healthypeople.gov/.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject
to the intergovernmental review requirements of Executive Order 12372
or Health Systems Agency review. Awards are made under the
authorization of Sections 301 and 405 of the Public Health Service Act
as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52
and 45 CFR Parts 74 and 92. All awards are subject to the terms and
conditions, cost principles, and other considerations described in the
NIH Grants Policy Statement. The NIH Grants Policy Statement can be
found at http://grants.nih.gov/grants/policy/policy.htm
The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the use of all tobacco products. In
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits
smoking in certain facilities (or in some cases, any portion of a
facility) in which regular or routine education, library, day care,
health care, or early childhood development services are provided to
children. This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.